When animals are exposed to different trace metals for prolonged time periods, each metal produces a biological response profile which specifically characterizes exposure to that metal. The objective of these studies is to assess and characterize response profiles based on a thorough understanding of subcellular mechanisms of metal toxicity and specifically to (1) define and correlate ultrastructural and biochemical responses in vivo which characterize exposure to toxic trace elements following prolonged exposure and (2) develop early, specific, and sensitive, biochemical testing procedures that may be used to evaluate human populations exposed to environmentally important trace elements. Specific metals and areas of interest include the biochemical effects of cadmium, manganese, arsenic, mercury, selenium, and lead on mitochondrial structure and function: Enzyme activities associated with mitochondrial membranes have been found to show early and pronounced changes in mitochondria of rats and mice following prolonged exposure to arsenic. Further development of these biochemical response profiles should permit a more basic understanding of the cellular mechanisms of metal toxicity and development of metal-specific biochemical testing procedures which accurately assess a biological response to these agents prior to overt toxicity.